Time of delivery among low‐risk women at 37–42 weeks of gestation and risks of stillbirth and infant mortality, and long‐term neurological morbidity

Abstract Background The most important knowledge gap in connection with obstetric management for time of delivery in term low‐risk pregnancies relates to the absence of information on long‐term neurodevelopmental outcomes. Objectives We examined risks of stillbirth, infant mortality, cerebral palsy (CP) and epilepsy among low‐risk pregnancies. Methods In this population‐based Swedish study, we identified, from 1998 to 2019, 1,773,269 singleton infants born between 37 and 42 completed weeks in women with low‐risk pregnancies. Poisson log‐linear regression models were used to examine the association between gestational age at delivery and stillbirth, infant mortality, CP and epilepsy. Adjusted rate ratios (RR) and 95% confidence intervals expressing the effect of birth at a particular gestational week compared with birth at a later gestational week were estimated. Results Compared with those born at a later gestation, RRs for stillbirth and infant mortality were higher among births at 37 weeks' and 38 weeks' gestation. The RRs for infant mortality were approximately 20% and 25% lower among births at 40 or 41 weeks compared with those born at later gestation, respectively. Infants born at 37 and 38 weeks also had higher RRs for CP (vs infants born at ≥38 and ≥39 weeks, respectively), while those born at 39 gestation had similar RRs (vs infants born at ≥40 weeks); infants born at 40 and 41 weeks had lower RRs of CP (vs those born at ≥41 and 42 weeks, respectively). The RRs for epilepsy were higher in those born at 37 and 38 weeks compared with those born at later gestation. Conclusions Among low‐risk pregnancies, birth at 37 or 38 completed weeks' gestation is associated with increased risks of stillbirth, infant mortality and neurological morbidity, while birth at 39–40 completed weeks is associated with reduced risks compared with births at later gestation.


| ME THODS
This study was based on singleton births in Sweden between 1998 and 2019 with data obtained from the Medical Birth Register. 17 This database contains information on antenatal, obstetric and neonatal care that is prospectively recorded on standardised forms on more than 98% of all births in Sweden. Using the personunique national registration numbers of mothers and infants, data from the Birth Register were linked to several national registries.
The nation-wide National Patient Register 18,19 includes diagnostic codes and procedures on hospital inpatient care since 1987 and hospital outpatient care from 2001. The Cause of Death Register includes information on all deaths in Sweden. 20 In the Medical Birth, Patient and Cause of Death Registers, diseases and ≥41 and 42 weeks, respectively). The RRs for epilepsy were higher in those born at 37 and 38 weeks compared with those born at later gestation.
Conclusions: Among low-risk pregnancies, birth at 37 or 38 completed weeks' gestation is associated with increased risks of stillbirth, infant mortality and neurological morbidity, while birth at 39-40 completed weeks is associated with reduced risks compared with births at later gestation.

K E Y W O R D S
gestational age, infant mortality, neurodevelopmental disorder, stillbirth, timing of delivery

Study question
What is the impact of time of delivery in low-risk pregnancies at ≥37 weeks' gestation on risks of stillbirth, infant mortality and neurological disorders in offspring?

What is already known
The time of delivery in low-risk pregnancies is of particular concern as the clinician must balance the higher risks of respiratory morbidity and other neonatal complications associated with early-term delivery with the risks of postmaturity. There is a critical knowledge gap concerning the time of delivery in low-risk women at ≥37 weeks' gestation and long-term outcomes.

What the study adds
Being born at 39 and 40 weeks reduces risks of stillbirth, infant mortality and cerebral palsy, indicating that 39+0 to 40+6 weeks is the optimum time for delivery for low-risk pregnancies.
deaths are, since 1997, coded using the Swedish version of the International Classification of Diseases, tenth revision (ICD- 10) 1997. Information on maternal education and country of origin was obtained from the Education Register and the Total Population Register, respectively. 21,22

| Study population
Between 1 January 1998 and 31 December 2019, we identified 2,119,175 singleton live births and stillbirths at ≥37 completed gestational weeks from the Medical Birth Register. We excluded births with missing information on personal identification numbers (n = 2296), sex, date of birth and maternal age (n = 3). We further excluded infants born at ≥43+0 weeks (n = 9103), those in breech presentation and infants of mothers with chronic diseases and selected pregnancy complications 21 (n = 334,504). All ICD-10 codes used in the analyses are shown in Table S1. The final study population included 1,773,269 births.

| Exposure
Gestational age (in completed weeks) was estimated using the following hierarchy: the date of early second trimester ultrasound (90.5%), the date of the last menstrual period (5.4%) and a postnatal assessment (4.1%). We evaluated outcomes at each gestational week by comparing delivery at a given gestational week with delivery at a later gestational week (i.e. expected management). The latter group thus included women who went on to have a spontaneous labour, an induction or a caesarean delivery at a later gestational age (a comparison more conducive to the clinical paradigm and better suited to guide clinical decision-making). Thus, the effect of delivery at 37 weeks was assessed by comparing outcome rates among births at 37+0 to 37+6 weeks with those among births at 38+0 to 42+6 weeks and so forth.
Infant mortality was defined as death within the first year after birth. Cases of CP and epilepsy were identified by the presence of one or more diagnostic codes for CP (ICD-10 code G80) or epilepsy (ICD-10 code G40) either in hospitalisation records or in outpatient visit records (diagnosis of epilepsy was restricted to the period after 27 days of age). Children with epilepsy who also had CP (n = 1169 infants) were not included in the epilepsy cohort. The date associated with the first record of epilepsy or CP was considered the date of diagnosis (up to 16 years of age).

| Covariates
Maternal characteristics examined included age at delivery, country of birth, education, cohabitation with a partner, parity, height and smoking during pregnancy. Mothers who reported daily smoking at the first antenatal visit and/or at 30-32 gestational weeks were classified as smokers. Information on onset of labour (spontaneous, induced or caesarean delivery) was obtained from obstetric records, and the year of delivery was examined to address temporal changes in obstetric practice.

| Statistical analysis
The distributions of maternal and infant characteristics were quantified for births occurring at each gestational week. We examined the association between gestational age and stillbirth, infant mortality, CP and epilepsy on both additive (risk difference) and multiplicative (risk ratio [RR]) scales, derived from fitting log-linear Poisson regression models with robust variance (using an identity link for the risk difference and a log link for the risk ratio). 23 In the multivariable analyses, estimates were adjusted for maternal factors (maternal age, height, country of origin, parity, education level and smoking), child's sex and year of birth. We also performed stratified analyses of feto-infant mortality (i.e. stillbirth and/or infant mortality), CP and epilepsy by onset of labour (spontaneous, caesarean delivery and induced). In this analysis, rates of outcomes at any gestational week within each onset of labour category were compared with rates of outcome among all births at subsequent gestational weeks.

| Causal mediation analysis
We considered asphyxia-related neonatal conditions (e.g. convulsions, meconium aspiration and hypoxic ischaemic encephalopathy; Table S2 lists the ICD codes used), diagnosed at 0-27 days of age, as potential mediators for the effect of gestational age on infant mortality, CP and epilepsy ( Figure S1, Tables S3 and S4). Therefore, we undertook causal mediation analyses based on a counterfactual framework 24 to disentangle the association between gestational age and the outcomes (i.e. total effect) into the natural direct effect (the association between gestational age and the outcomes [infant mortality, CP and epilepsy] in the absence of asphyxia-related conditions) and the natural indirect effect (the association operating through the mediators). 25 We also estimated the controlled direct effect, which provided an estimate of the effect of gestational age on the outcomes that is not mediated through asphyxia-related conditions. We additionally estimated the proportion of the total effect (on the RR scale) between gestational age and the outcome(s) that was mediated through asphyxia-related conditions. All 95% CI estimates were based on 1,000 bootstrap samples. Log-linear regression models and the mediation analysis were carried out in SAS (version 9.4; SAS Institute) using GENMOD and the CAUSALMED procedures, respectively.

| Missing data
Since some of the covariates had missing values, we imputed missing data through multiple imputation using a chained equations approach. 26 We assumed that the pattern of missing data was 'missing at random' and created 10 imputed data sets (after 200 burn-in iterations). Results from 10 multiple imputation cycles were combined with the use of PROC MIANALYZE in SAS.

| Sensitivity analysis
We performed several sensitivity analyses. First, since mediation methods were developed under a strict no-unmeasured confounding assumption, 24 we examined the robustness of causal effects to unmeasured confounders, by estimating an E-value (defined as the maximal strength of association that an unmeasured confounder would need to have with the exposure and the outcome, to fully explain away an observed exposure-outcome association). 27 Second, since information on body mass index (BMI) was missing in 149,013 (8.4%) women and information on major congenital malformations was only available among live births, adjustment for BMI, malformations (Table S2) and birthweight-for-gestational age was carried out in sensitivity analyses restricted to live births.
BMI was calculated using weight measured at registration for antenatal care and self-reported height. Birth weight-for-gestational age was estimated using the sex-specific Swedish foetal growth reference. 28 Third, women with hypertensive disorders of pregnancy were included in the expectant management group in sensitivity analyses, as gestational hypertension and preeclampsia can occur later in pregnancy and are a potential complication of expectant management.
Fourth, as death prior to the diagnosis of CP or epilepsy could preclude a child from being diagnosed with either condition, we additionally quantified the adjusted association between gestational age at birth and a composite outcome of death or CP (i.e. stillbirth, infant death or CP) and a composite outcome of death or epilepsy (i.e. stillbirth, infant death or epilepsy). Fifth, to account for the varying lengths of follow-up and since the probability of being diagnosed with CP and epilepsy changes with age, we calculated hazard ratios (HRs) and 95% CIs using Cox proportional hazard models. Stratified analyses by parity (0 or ≥1) were performed to investigate whether parity modified the association between gestational age and the composite outcomes.

| Ethics approval
The study was approved by the Research Ethics Committee at the Karolinska Institutet, Stockholm, Sweden (No. 2020-01545).

| RE SULTS
Mothers of infants born at 37-38 weeks were more likely to be younger (≤19 years), to smoke, to be shorter (≤159 cm), underweight (BMI < 18.5 kg/m 2 ), multiparous (parity ≥4), to have a lower educational level and to have had a caesarean delivery, while infants born at 37-38 weeks of gestation were more often small-for-gestational age (<3rd percentile, Table 1). Among births at a given gestational week, stillbirth rates decreased from 37 to 40 weeks before increasing at 41 and 42 weeks' gestation ( Figure 1). Compared with births at a later gestational week, risks of stillbirth were higher among births at 37 weeks of gestation and 38 weeks of gestation. The adjusted risk ratio for stillbirth among births at 39 weeks' gestation was similar to the risk of stillbirth among births at ≥40 weeks ( Table 2). The absolute rate differences for stillbirth were lower among births that occurred at 40 weeks and at 41 weeks compared with those that occurred at >40 and >41 week's gestation, respectively.
Among live births at a given gestational week, infant mortality rates decreased from 37 to 40 weeks, before increasing at 41 and 42 weeks' gestation ( Figure 1). Adjusted risks and the absolute risk differences in infant mortality were higher among births at 37 and 38 weeks of gestation compared with live births at a later gestational week ( Table 2). The adjusted risks for infant mortality were 20% and 25% lower among live births that occurred at 40 and 41 weeks, compared with those that occurred at >40 and >41 week's gestation, respectively.
The rate of CP was lowest among live births at 40 weeks' gestation, with the highest rates at 37 weeks and at 42 weeks ( Figure 1). Infants born at 37 weeks and 38 weeks had higher adjusted rate ratios and absolute risk differences for CP than infants born at ≥38 weeks and ≥39, respectively. The risk for CP was not elevated among infants born at 39 weeks, compared with infants born at ≥40 weeks. Infants born at 40 weeks and infants born at 41 weeks had lower risks for CP compared with those born later (

| Causal mediation analyses
We examined the impact of asphyxia-related conditions on the association between gestational age and infant mortality, CP and epilepsy (

| Sensitivity analyses
Our primary results were unchanged using multiple imputations of missing data (Table S5). Adjustment for maternal BMI, major congenital malformations and birthweight-for-gestational age among live births did not substantially influence the results (Table S6).
Including women diagnosed with pregnancy-induced hypertensive disorders in pregnancy in the expectant management group further strengthened the associations between gestational age at birth and the outcomes (Table S7). Analyses of associations between gestational age at birth and composite death or CP (Table S8)  enhanced precision of the estimates. In the sensitivity analyses, the E-value for the RR and the lower 95% CI were greater in magnitude compared with the observed estimates. These results suggest that the casual mediation parameters were robust to unmeasured confounding (Table S10). Hazard ratios from Cox regression showed similar results as the primary analyses, indicating that the effects of loss to follow-up, that is, death or emigration, were minimal (Table S11). Lastly, stratified analyses by parity showed similar findings among primiparae and multiparae women. However, the risk of CP was not increased at any gestation among live births to primiparous women (Table S12).

| Principal findings
In this nationwide cohort study of low-risk pregnancies at term gestation, we found that risks of stillbirth, infant mortality, CP and epilepsy were increased among births at 37 and 38 weeks' gestation, compared with births at ≥38 weeks and ≥39 weeks, respectively.
There were no differences in risks among births at 39 weeks' gesta-

| Strengths of the study
This study has several strengths. The population-based study design, together with the prospectively and independently collected information on exposure and outcomes and other high-quality registry data, minimised the possibility of selection and information bias.
Our analyses compared the rates of outcomes of births at each gestational week with the rates of outcomes among those born at subsequent gestational weeks. This allowed us to measure the effect of early-term delivery versus expectant management at different gestational weeks and to directly address the question most relevant for clinical decision-making and pregnancy management among low-risk women. In addition, we quantified the effects on composite outcomes that included death or CP, and death or epilepsy (thereby addressing the issues related to outcome-dependent censoring and competing risks). 29

| Limitation of the data
Some study limitations also deserve consideration. Despite limiting the study to low-risk pregnancies, it is likely that a higher pro-

| Interpretation
Consistent with our findings, increased risks of neonatal mortality, intellectual deficits, poorer school performance and long-term neurological disorders have been found in children born at early term (37-38 weeks). [31][32][33][34] Stillbirth risk increases with gestational age in term and especially post-term pregnancies, and foetal growth restriction likely explains a part of this increased risk. 35 Among births at a specific gestational week, an approximate U-shaped pattern is evident in the gestational age-specific risks of stillbirth, infant mortality, CP and epilepsy, with the highest risks at 37 weeks and 42 weeks. 34,36 These patterns arise because infants born at early term may be vulnerable due to physiological immaturity, while postterm infants may be compromised due to post-maturity. While some adverse outcomes among early-term births may be attributed to immaturity, a large proportion are likely a consequence of pregnancy complications or underlying conditions that led to early delivery. A related issue arises because low-risk women in non-experimental studies can have differential distributions of pregnancy complications by place of birth, gestational age and other factors. 37 This makes non-experimental studies less suitable than randomised trials 9 for identifying an optimal gestational age for delivery. Still, feasibility issues may limit the number of options explored with experimental designs.
The findings of this study add to the growing evidence that infants born between 39 and 40 weeks have the best perinatal and long-term neurodevelopmental outcomes. 7,8,11,38,39 In our study, the TA B L E 2 Gestational age at birth and relative risks of stillbirth, infant mortality, cerebral palsy and epilepsy among singleton term births in Sweden, 1998Sweden, ,2019  Note: RRs are adjusted for maternal age, country of origin, education level, cohabitation with a partner, parity, height, smoking during pregnancy, child's sex and year of delivery. All 95% CI estimates are based on 1000 bootstrap resamples. The exposure-mediator interaction term was retained in the mediation analysis. CI, confidence intervals; RR, risk ratio. a Asphyxia-related neonatal conditions included convulsions, meconium aspiration and hypoxic ischemic encephalopathy.
rates of stillbirth, infant mortality and CP were higher among infants born at 41 and 42 weeks' gestation than in infants born at 40 weeks, whereas the rate of epilepsy was not. Asphyxia-related conditions explained part of the increased risk of infant mortality and CP at late-term (41-42 weeks) gestation. Morbidity due to late gestation diseases, such as hypoxic ischaemic encephalopathy, meconium aspiration and neonatal seizures, showed a pronounced increase from term gestation onwards and contributed to the pathogenesis of infant mortality and neurological complications. 34,40,41 Animal and human studies show that the ability of the utero-placental system to support the foetus declines with advancing gestation 4 : although blood flow to the uterus increases as pregnancy advances, normalised blood flow (i.e. blood flow per unit foetal weight) falls. 42,43 These changes likely underlie the increase in adverse perinatal outcomes, including intrauterine growth restriction, stillbirth, neonatal death and neurological morbidity at late-term and post-term gestation, leaving 39 and 40 weeks' gestation as the optimal time for delivery.

| CON CLUS IONS
In summary, our findings provide evidence to support the propo-

AUTH O R CO NTR I B UTI O N
NR had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis (guarantors of this work). NR, GM and KSJ conceived and designed the study. All authors interpreted the data and critically revised the manuscript for important intellectual content. NR drafted